A reliable, highly reproducible model of bladder cancer in Fischer rats using the carcinogen N-(4-(5-nitro-2-furyl)-2-thiazolyl) formamide (FANFT) was developed. The natural history and the reversibility of irreversibility of early lesions were determined. Of numerous morphologic parameters examined, utilizing light and electron microscopic (EM) techniques, visualization with scanning EM of pleomorphic microvilli on the luminal surface of bladder epithelial cells (instead of the characteristic microridge system of normal superficial cells) most closely correlated with irreversibility of early stage of carcinogenesis in this model. Comparable changes were seen on exfoliated bladder epithelial cells in urine samples from rats with irreversible non-invasive lesions after ten weeks of FANFT, preceding recognizable light microscopic evidence of cancer in cytologic preparations by 50 weeks. We propose to determine the diagnostic and prognostic significance of pleomorphic microvilli is seen with SEM by further study of the FANFT-Fischer rat model, by studying this phenomenon in other experimental bladder cancer models and non-neoplastic proliferative lesions of the bladder, and by the study of human tissue samples and cytologic material. We have established 3 rat bladder tumor lines in culture, either following or concurrent with the establishment of serially transplantable lines of the same FANFT-induced tumors in Fischer rats. We propose to expand these studies, establishing additional in vivo and in vitro lines. The in vitro model, particularly with the same tumor being available for studies in vivo, will permit further evaluation of ultrastructural, biochemical and immunological aspects of bladder tumors. We would also propose to investigate the effect of tumor-host interaction on prognosis of primary and metastatic disease. The development of an in vitro model of bladder carcinogenesis, to complement our in vivo model, is also planned.